Project Summary The prevalence of low bone mass diseases, such as osteoporosis, is growing each year as the baby boomer generation ages. Better anabolic and/or anti-catabolic agents to combat this problem are needed. The mechanical loading environment in bone plays a crucial role in bone mass. One key molecular pathway in the bone response to mechanical load is Wnt signaling. The Wnt co-receptors Lrp5 and Lrp6 are involved in regulating bone development and maintaining bone mass, and while Lrp5 is known to be necessary for mechano-response, it is unclear if Lrp6 is involved specifically in mechanotransduction. Additionally, the function of the intracellular downstream mediator of Wnt signaling, ?-catenin, in the mechanical response is not well defined. This proposal aims to address (1) the role of osteocytic Lrp6 in bone mechanical signaling and (2) the susceptibility to disuse-induced bone loss following constitutive activation of ?- catenin in osteocytes. To test aim 1, mice will be induced at 16 weeks of age for osteocyte -specific Lrp6 deletion and will be subjected to mechanical load by ulnar loading. Four weeks later, ulna will be analyzed for bone formation parameters by dynamic histomorphometry. It is hypothesized that these Lrp6- deficient mice will remain fully responsive to mechanical load, although mice with deletion of Lrp5 do not respond to mechanical loading. In aim 2, mice with inducible osteocyte-specific ?-catenin gain-of-function will be subjected to disuse. Following induction of ?-catenin activation at 12 weeks of age, mice will be subjected to disuse by a muscle paralysis model (botox) or tail suspension. Following 4 weeks of disuse, bones will be analyzed for changes in bone mass and bone formation rates. Gene transcription changes by RNAseq will provide novel insights into the pathways altered by disuse in bone. It is hypothesized that constitutive activation of ?-catenin in osteocytes will protect mice from disuse-induced bone loss, unlike their wild-type counterparts. Characterization of these molecules in the response of bone in increased loading or disuse situations will lead to better understanding of the role of the Wnt pathway in loading and the potential for new drug therapies for osteoporosis and other low bone mass diseases.